Tubulointerstitial fibrosis is a poor prognostic indicator and common final pathway in the development of end-stage renal disease irrespective of the underlying cause, ultimately leading to the destruction of renal tissue and irreversible loss of renal function. As the incidence of patients with newly diagnosed chronic kidney disease and ESRD is rising, sophisticated understanding of underlying mechanisms and identification of new molecular targets to control renal fibrogenesis is fundamental in the development of new therapies to reverse this disturbing trend. Peri-tubular capillary loss is a hallmark of progressive renal disease and results in reduced blood flow that limits oxygen delivery to the kidney leading to chronic tubulointerstitial hypoxia. Key mediators of cellular adaptation to hypoxia are Hypoxia-Inducible-Factor (HIF)-1 and -2, basic-helix-loop- helix transcription factors, mostly known for their ability to regulate vascular remodeling, erythropoiesis, and energy metabolism. Here we hypothesize that hypoxia represents an early and initiating event in the development and progression of kidney disease, and that activation of HIF signaling promotes epithelial to mesenchymal transition (EMT) and renal fibrogenesis. Because the biological functions of renal HIF-1 and HIF-2 appear to be cell-type dependent, we propose studies, which a) investigate the role of individual HIF transcription factors in the pathogenesis of progressive renal disease in a cell-type specific context in vivo and b) are aimed at the identification of relevant HIF regulated genes and signaling pathways. Specifically we propose studies, which include: a) animal models of progressive renal disease in conjunction with Cre-loxP mediated recombination to achieve cell-type specific inactivation of HIF-1a and HIF-2a, b) studies that examine specific HIF target genes and their role in EMT and fibrogenesis in vitro and in vivo, c) gene regulatory studies, and d) studies utilizing state of the art gene expression and promoter arrays to identify relevant HIF target genes. Overall, this grant aims at establishing a research program, which investigates the effects of HIF activation on the expression of genes and signaling networks that are critical in the development and progression of renal disease. The proposed studies will have immediate clinical implications as they strongly encourage therapies that aim at improving the balance between renal oxygen delivery and consumption to halt the progression of renal fibrosis. PUBLIC HEALTH RELEVANCE This grant investigates the role of a low oxygen environment in the progression of chronic kidney disease. A main focus is on signaling through the Hypoxia-Inducible Factor (HIF) pathway. Identification and characterization of molecular pathways that are activated by hypoxia has the potential to provide the basis for new therapeutic approaches to halt the progression of renal scarring.